Echinocandins are a first-line therapy for Candida infections through their ability to inhibit the synthesis of polymer β-(1,3)-d-glucan. However, there has been an emergence of multidrug-resistant fungal species necessitating the development of novel antifungal agents to combat invasive fungal infections. SCY-247, a second-generation glucan synthase inhibitor of the triterpenoid class (fungerps), is currently being developed as a potential therapy option. We determined the pharmacokinetics (PKs) of SCY-247 following oral (gavage) administration in mice and evaluated the efficacy of SCY-247 in a murine model of hematogenously disseminated candidiasis caused by Candida albicans. Plasma concentrations of SCY-247 were measurable through the last collected time point in all dose groups. Mean concentrations of SCY-247 increased with dose levels, with concentrations of SCY-247 higher after multiple doses than after a single dose. Treatment with SCY-247 resulted in decreased fungal burden and improvement in survival rates against C. albicans disseminated infection. Treatment with 10 mg/kg of body weight of SCY-247 showed a significant reduction in CFU compared with the untreated control (3-log decrease on average) (P = 0.008). Similarly, 40 mg/kg SCY-247 demonstrated a statistically significant reduction in kidney CFU compared with untreated mice (average log CFU ± SD of 2.38 ± 2.58 versus 6.26 ± 0.51; P = 0.001). Mice treated with SCY-247 at 40 mg/kg exhibited a 100% survival rate at the end of the study, contrasted with 62.5% (5 of 8) survival rate in untreated mice. The results of this investigation indicate that SCY-247 is a promising novel anti-fungal agent with activity against Candida infections.

中文翻译：

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第二代 Fungerp 类似物 SCY-247 在血液传播的白色念珠菌小鼠模型中显示出强大的体内活性

棘白菌素是用于第一线疗法念珠菌感染通过它们抑制的聚合物β-（1,3）的合成的能力- d -葡聚糖。然而，已经出现了耐多药真菌物种，需要开发新型抗真菌剂来对抗侵袭性真菌感染。SCY-247 是第二代三萜类（真菌）葡聚糖合酶抑制剂，目前正在开发中作为一种潜在的治疗选择。我们确定了小鼠口服（强饲）给药后 SCY-247 的药代动力学 (PK)，并评估了 SCY-247 在由白色念珠菌引起的血行播散性念珠菌病鼠模型中的功效. 在所有剂量组中，通过最后收集的时间点可测量 SCY-247 的血浆浓度。SCY-247 的平均浓度随剂量水平而增加，多次给药后 SCY-247 的浓度高于单次给药后。用 SCY-247 治疗导致真菌负担减少，并提高了对抗白色念珠菌播散性感染的存活率。与未处理的对照相比，用 10 mg/kg 体重的 SCY-247 处理显示 CFU 显着降低（平均降低 3-log）（P = 0.008）。同样，与未治疗的小鼠相比，40 mg/kg SCY-247 在统计学上显着降低了肾脏 CFU（平均 log CFU ± SD 为 2.38 ± 2.58 与 6.26 ± 0.51；P = 0.001）。用 40 mg/kg 的 SCY-247 治疗的小鼠在研究结束时表现出 100% 的存活率，而未治疗小鼠的存活率为 62.5%（8 只中的 5 只）。这项研究的结果表明 SCY-247 是一种有前途的新型抗真菌剂，具有抗念珠菌感染的活性。